Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor.

Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor" was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.

A novel lignin degradation bacteria-Bacillus amyloliquefaciens SL-7 used to degrade straw lignin efficiently.

Using tobacco straw (Ts) and lignin as the sole carbon source, a strain was isolated from Ts and identified as Bacillus amyloliquefaciens SL-7 by 16S rDNA gene-sequencing technology.7-day incubation of Bacillus amyloliquefaciens SL-7 can reduce the chemical oxygen demand (COD) by 69.35% in lignin mineral salt medium. The activity of Manganese peroxidase (MnP) reached maximum level 258.57 U L-1, and Lignin peroxidase (Lip) was 422.68 U L-1 at 4th day. The highest Laccase (Lac) activity (55.95 U L-1) was observed at 3th day. After straw-liquid fermentation degradation of 15 days, the bacterial could degrade 28.55% lignin of the straw which was close to that of fungi. Compared with the control group and effective microorganisms (EM) group, the lignin degradation rate in Bacillus amyloliquefaciens SL-7 group increased by 22.26% and 11.70% at 41-day compost fermentation of tobacco straw. These show the strain has strong lignin degradation performance.

Design, synthesis and anticancer activity of naphthoquinone derivatives.

Basis on molecular docking and pharmacophore analysis of naphthoquinone moiety, a total of 23 compounds were designed and synthesised. With the help of reverse targets searching, anti-cancer activity was preliminarily evaluated, most of them are effective against some tumour cells, especially compound 12: 1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl-4-oxo-4-((4-phenoxyphenyl)amino) butanoate whose IC50 against SGC-7901 was 4.1 ± 2.6 µM. Meanwhile the anticancer mechanism of compound 12 had been investigated by AnnexinV/PI staining, immunofluorescence, Western blot assay and molecular docking. The results indicated that this compound might induce cell apoptosis and cell autophagy through regulating the PI3K signal pathway.

Binding patterns and structure-activity relationship of CDK8 inhibitors.

A major goal of medicinal chemists is to identify and validate novel and effective kinase targets for treatment of cancer. Recent studies have shown that cyclin-dependent kinase 8 (CDK8) is a target for treatment of colorectal, breast, melanoma, and prostate cancers. The crystal structure of CDK8 has been reported, and eutectic interactions have been identified for 24 compounds that target CDK8. To more effectively develop CDK8 inhibitors, particularly those with improved selectivity, we summarized the structure, structure-activity relationships, and binding information of typical CDK8 inhibitors, which may serve as a reference for development of novel CDK8 inhibitors.

Lipopolysaccharide-induced TNF-α factor in grass carp (Ctenopharyngodon idella): evidence for its involvement in antiviral innate immunity.

Lipopolysaccharide-induced TNF-α factor (LITAF), which participates in innate immune response and regulates TNF-α transcription, has been identified and characterized in various organisms. In a study to screen interacting cellular proteins with grass carp reovirus using yeast two-hybrid system, a grass carp homologue of LITAF was identified to bind the NS26 protein encoded by the S11 genomic fragment of Grass carp reovirus (GCRV). In this study, grass carp LPS-induced TNF-α factor gene (designated as CiLITAF) was cloned and sequenced from the cDNA library constructed for the yeast two-hybrid screening. The CiLITAF cDNA contained an open reading frame (ORF) of 483 bp encoding a polypeptide of 161 amino acids with an estimated molecular mass of 17.0 kDa. In CIK cells infected with GCRV or treated with poly (I:C), transiently stimulated transcription of CiLITAF mRNA was noticed at 8 h post infection or poly (I:C) treatment. Grass carp TNF-α (CiTNFα) transcriptional level was also transiently induced to a high level following the stimulation of CiLITAF in these in vitro tests. In vivo analysis further showed that, significantly up-regulated transcriptional expression of both CiLITAF and CiTNFα were detected in the spleen tissue as early as 48 h post challenge with GCRV. This study thus characterized CiLITAF as an inducible gene responding to viral infection.